HRP20020741A2 - Method for the preparation of citalopram - Google Patents

Description

This invention relates to a method of preparing the well-known antidepressant citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.

Previous state of the profession

Citalopram is a well-known antidepressant that has been on the market for several years and has the following structure:

[image]

It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, and therefore has an antidepressant effect. The antidepressant activity of this compound has been described in several publications, eg J. Hyttel Prog. Neuro-Phychopharmacol. & Biol. Psychiatrist. 1982, 6, 277-295 and A. Gravem Acta Psychiatr. Scand. 1987, 75, 478-486. In addition, the compound has been shown to be effective in the treatment of dementia and cerebrovascular disorders, EP-A-474580.

Citalopram was first described in DE 2,657,013, corresponding to US 43,136,193. That patent publication describes the preparation of citalopram in one way and suggests a further method that can be used to prepare citalopram.

According to the described procedure, the corresponding 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran-carbonitrile is reacted with 3-(N,N-dimethylamino)propyl chloride in the presence of methylsulfinylmethyl as a condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with copper cyanide.

International patent application no. WO 98/019511 describes a process for the production of citalopram in which 4-(cyano, alkyloxycarbonyl or alkylaminocarbonyl)-2-hydroxymethyl-phenyl-(4-fluorophenyl)methanol is subjected to ring closure. The resulting 5-(alkyloxycarbonyl or alkylaminocarbonyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran is converted to the corresponding 5-cyano derivative, and this 5-cyano derivative is then alkylated with (3-dimethylamino)propyl halide to give received citalopram.

Now, unexpectedly, it has been shown that citalopram can be produced by a new, convenient process in which 5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran is alkylated with a compound that can be converted to a dimethylaminopropyl group.

The alkylation process according to this invention has a special advantage because the formation of by-products due to the polymerization of the alkylating agent is avoided, which enables the reduction of the amount of alkylating agent to be used. The process according to the present invention also enables high recovery.

Summary of the invention

This invention relates to a method of preparing citalopram, which consists in the reduction of a compound of the formula

[image]

where X is a cyano group or a group that can be converted to a cyano group,

and when X is not a cyano group, this is followed by conversion of X to a cyano group, and isolation of citalopram base or its pharmaceutically acceptable acid salt.

In one embodiment of the present invention, a compound of formula (III) can be prepared

by the reaction of the compound of the formula

[image]

where X is according to the above definition, with the compound of the formula

[image]

and if X is not cyano optionally followed by conversion of the X group to a cyano group and then dehydration to form a compound of formula (III), and if X is not cyano optionally by conversion of the X group to a cyano group.

In another embodiment, a compound of formula (III) can be prepared by reacting a compound of formula (I) with a compound of formula

[image]

and if X is not cyano, which is optionally followed by the conversion of the group X to the cyano group, then by dehydration to form the compound of formula (III) and if X is not cyano by the optional conversion of the group X to the cyano group.

In the third embodiment, the compound of formula (III) is prepared by reacting the compound of formula (I) with the compound of formula

[image]

where Y is a suitable residue to form a compound of the formula

[image]

and if X is not cyano followed by optional conversion of the X group to a cyano group, by peroxidation of the double bond to form an epoxide, and if X is not cyano optionally by conversion of the X group to a cyano group, followed by reaction with dimethylamine or its salt and then dehydration to form of the compound of formula (III) and if X is not cyano optionally by converting the X group to a cyano group.

In another aspect, the present invention provides novel intermediates of general formulas (III) and (V).

In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram produced by the method of the present invention.

Suitable residues Y can be a halide or sulfonate of the formula -O-SO2-R0, where R0 is alkyl, alkenyl, alkynyl or optionally alkyl substituted aryl or aralkyl. It is customary for R 0 to be methyl or p-methylphenyl.

Groups X that can be converted to a cyano group can be selected from halogen, -O-SO2-(CF)n-CF3, where n represents 0-8, -CHO, -COOR', -CONR'R'', -NHR ''', wherein R'' and R'' are hydrogen, alkyl, alkenyl or alkynyl or optionally alkyl substituted aryl or aralkyl, and R''' is hydrogen or alkylcarbonyl or X is an oxazoline or thiazoline group of the formula

[image]

wherein U represents O or S;

R 12 - R 14 are each independently selected from hydrogen and alkyl or R 12 and R 13 together form a C 2-5 alkylene chain thereby forming a spiro ring; R 10 is selected from hydrogen and alkyl, R 11 is selected from hydrogen, alkyl, a carboxy group or a derivative thereof, or R 10 and R 11 together form a C 2-5 alkylene chain thereby forming a spiro ring.

X can be any other group that can be converted to a cyano group.

The alkylation process when the compound of formula I is reacted with a compound of formula (IIa), (IIb) or (IIc) is conveniently carried out by treating the compound of formula (I) with a base such as, for example, LDA (lithium diisopropylamine), LiHMDS (lithium hexamethyldisilas), NaH , NaHMDS (hexamethyldisilasan sodium) and metal alkoxides such as NaOMe, KOMe, LiOMe, NaOtertBu, KotertBu and LiOtertBu in an aprotic organic solvent such as THF (tetrahydrofuran), DMF (dimethylformamide), NMP (N-methylpyrrolidone), ethers such as diethyl ether or dioxalan, toluene, benzene or alkanes and their mixtures. The thus obtained anion is then reacted with a compound of formula (IIa), (IIb) or (IIc).

The reaction of a compound of formula (I) with a compound of formula (IIa), (IIb) or (IIc) is conveniently carried out under anhydrous conditions.

Dehydration of the alcohol intermediate formed by the reaction of the compound of formula (I) with the compound of formula (IIa) or (IIb) to form the compound of formula (III) can be carried out with any suitable dehydrating agent, for example with p-toluenesulfonic acid in toluene or with mineral salts SOCl2, POCl3, PCl5, etc.

Peroxidation of the alkene double bond in a compound of formula (V) to form an epoxide can be carried out using tertBuOOH, organic peracids, dimethyldioxirane, NaOCl, I2/Ago, microorganisms, etc. After reaction with dimethylamine or its salt, the resulting compound is subjected to dehydration using any suitable dehydrating agent. agent, eg by p-toluenesulfonic acid in toluene or by SO Cl2, POCl3, PCl5, mineral salts, etc.

The reduction of the compound of formula (III) is conveniently carried out in the presence of Pd/C, Pt/C or Rh/C as a catalyst.

When X is halogen or CF3-(CF2)n-SO2-O-, where n is 0-8, conversion to the cyano group can be accomplished by reaction with a cyanide source, eg KCN, NaCN, CuCN, Zn(CN)2 or (R15)4NCN, where (R15)4 denotes four groups, which may be the same or different, and are selected from hydrogen and straight chain or branched alkyl, in the presence of a palladium catalyst and a catalytic amount of Cu+ or Zn2+, or with Zn(CN) 2 in the presence of a palladium catalyst. Conversion of a compound in which X is halogen or CF3-(CF2)n-SO2-O-, where n is 0-8, by reaction with a cyanide source in the presence of a palladium catalyst, can be carried out as described in WO 0013648.

When X represents Cl or Br the conversion to the cyano group can also be carried out by reaction with a source of cyanide, eg KCN, NaCN, CuCN, Zn(CN)2 or (R15)4NCN, where (R15)4 denotes four groups, which can be the same or different, and are selected from hydrogen and straight chain or branched alkyl, in the presence of a nickel catalyst. Conversion of a compound in which X is halogen or CF3-(CF2)n-SO2-O-, where n is 0-8, by reaction with a cyanide source in the presence of a nickel catalyst can be carried out as described in WO 001192.

The reactions can be carried out in any suitable solvent as described in Sakakibara et al. Bull. Chem. Soc. Jpn., 61, 1985-1990 (1988). Preferred solvents are acetonitrile, ethyl acetate, THF, DMF or NMP.

When X is an oxazoline or thiazoline of formula (VI), conversion to a cyano group can be carried out as described in WO 0023431.

When X represents CHO, conversion to a cyano group can be accomplished by converting the formyl group to an oxime or similar group by reaction with the reagent R16-V-NH2, where R16 is hydrogen, alkyl, aryl, or heteroaryl, and V is O, N, or S, after followed by dehydration with a common dehydrating agent, eg, thionyl chloride, acetic anhydride/pyridine, pyridine/HCl, or phosphorus pentachloride.

Preferred reagents R16-V-NH2 are hydroxylamine and compounds where R16 is alkyl or aryl and V is N or O.

When X represents –COOH the conversion to the cyano group can be carried out via the corresponding acid chloride or ester and amide.

The acid chloride is usually obtained by treating the acid with POCl 3 , PCl 5 , or SOCl 2 dry or in a suitable solvent, such as toluene or toluene containing a catalytic amount of N,N-dimethylformamide. The ester is obtained by treating the acid with an alcohol, in the presence of an acid, preferably a mineral acid or a Lewis acid such as HCl, H2SO4, POCl3, PCl5 or SOCl2. Alternatively, the ester can be obtained from the acid chloride by reaction with an alcohol. The ester or acid chloride is then converted to the amide by amidation with ammonia or an alkylamine, preferably t-butyl amine.

Conversion to the amide can also be carried out by reacting the ester with ammonia or an alkylamine under pressure and heating.

The amide group is then converted into a cyano group by dehydration. The dehydrating agent can be any suitable dehydrating agent, and the optimal agent can be readily determined by one skilled in the art. Examples of suitable dehydrating agents are SOCl 2 , POCl 3 and PCl 5 , preferably SOCl 2 .

In a particularly preferred embodiment, the carboxylic acid is reacted with an alcohol, preferably ethanol, in the presence of POCl3 to give the corresponding ester, which is then reacted with ammonia to give the corresponding amide, which is then reacted with SOCl2 in toluene containing a catalytic amount of N,N-dimethylformamide.

Alternatively, the compound in which X represents –COOH can be reacted with chlorosulfonyl isocyanate to give a nitrile or it can be treated with a dehydrating agent and sulfonamide as described in WO 0044738.

When X represents –NHR''', where R''' is hydrogen, conversion to cyano is preferably carried out by diazotization followed by reaction with CN-. The use of NaNO2 and CuCN and/or NaCN is most preferred. When R"" is alkylcarbonyl, the compound is first subjected to hydrolysis to give the corresponding compound in which R"" represents H, which is then converted as described above. Hydrolysis can be carried out in an acidic or alkaline environment.

The starting material of the formula (I) in which X is halogen can be prepared according to the description in GB 1526331, the compounds of the formula (I) in which X means –O-SO2-(CF2)n-CF3 can be prepared analogously to the compounds described in WO 99 /00640, compounds of formula (I) in which X is an oxazoline or thiazoline group can be prepared analogously to the compounds described in WO 0023431, compounds in which X is formaldehyde can be prepared analogously to the compounds described in WO 99/30548, compounds in which X means –COOH, and the ester and their amides can be prepared analogously to the compounds described in WO 98/19511, and the compounds of formula I containing NHR''' can be prepared analogously to the compounds described in WO 98/19512.

The reaction conditions, solvents, etc. used for the reactions described above are conventional conditions for such reactions and can be readily determined by one skilled in the art.

The starting material of formula (I) in which X is cyano can be prepared as described in US Pat. No. 4,136,193 or as described in WO 98/019511.

Compounds of formula (IIa), (IIb) and (IIc) are commercially available or can be prepared from commercially available starting materials in a conventional manner.

Citalopram appears on the market as an antidepressant in the form of a racemate. However, the active S-enantiomer of citalopram will soon be introduced to the market.

S-citalopram can be prepared by chromatographic separation of optically active isomers.

In all specifications and claims, the term alkyl refers to a branched or unbranched alkyl group having one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl- 2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.

Similarly, alkenyl and alkynyl mean such groups having two to six carbon atoms, including one double or triple bond, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

The term aryl refers to a mono- or bicyclic carbocyclic aromatic group, such as phenyl and naphthyl, especially phenyl.

The term aralkyl refers to aryl-alkyl, wherein aryl and alkyl are as defined above.

Optionally alkyl substituted aryl and aralkyl refers to aryl and aralkyl groups that can optionally be substituted with one or more alkyl groups.

Halogen means chlorine, bromine or iodine.

Citalopram can be used as the free base, preferably in crystalline form, or as a pharmaceutically acceptable acid salt thereof. Salts formed from organic or inorganic acids can be used as acid salts. Examples of such organic salts are those with maleic, fumaric, benzoic, ascorbic, amber, oxalic, bimethylene salicyl, citric, gluconic, lactic, malic, almond, cinnamic, citra-conic, aspartic, stearic, palmitic, itaconic, glycolic, p -amino-benzoic, glutamic, benzene sulfonic and theophylline acids, as well as 8-halotheophyllines, eg 8-brotheophylline. Examples of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The acid salts of citalopram can be prepared according to procedures known in the art. The base is reacted either with a calculated amount of acid in a water-miscible solvent, such as acetone or ethanol, and then the salt is isolated by concentration and cooling, or with an excess of acid in a water-immiscible solvent, such as ethyl ether, ethyl acetate or dichloromethane, at to which the salt separates by itself.

The pharmaceutical compositions of the present invention may be administered in any suitable manner and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, and parenterally in the form of conventional sterile injectable solutions.

The pharmaceutical formulations according to the present invention can be prepared by methods customary in the art. For example, tablets may be prepared by mixing the active substance with conventional excipients and/or diluents and then compressing the mixture in a conventional tableting machine. Examples of excipients or diluents are: starch flour, potato starch flour, talc, magnesium stearate, gelatin, lactose, binders and the like. Any auxiliaries or additives, color, aroma, preservatives, etc. can be used provided they are compatible with the active substances.

Solutions for injection can be prepared by dissolving active substances and possible additives in part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling it into suitable ampoules or vials. Any suitable additives used in the art, such as tonicity agents, preservatives, antioxidants, etc., may be added.

This invention is further illustrated by the following examples.

Example 1

A solution of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (4.8 g, 0.02 mol) in THF (50 mL) was added dropwise to a solution of LDA (butyl lithium 1.6 M ( 15 mL), diisopropylamine 2.6 g) at -30°C in a nitrogen atmosphere. After stirring for 10 minutes at -30°C, a solution of the compound of formula (IIa), (IIb) or (IIc) (0.02 mol) in THF (25 mL) was added dropwise and allowed to warm to room temperature, and then mixed for another 60 minutes. The reaction was then quenched with ice, extracted with toluene (3 x 50 mL), washed with water (50 mL) and concentrated under reduced pressure. The precipitate was purified by silica gel chromatography using n-heptane/EtOAc mixtures as eluent.

Claims (7)

1. The method of preparation of citalopram characterized by the fact that it contains the reduction of the compound of the formula [image] wherein X is a cyano group or a group that can be converted to a cyano group and wherein X is not a cyano group followed by conversion of X to a cyano group and isolation of citalopram in the form of a base or a pharmaceutically acceptable salt thereof. 2. The method according to claim 1, characterized in that the compound of the formula (III) is prepared by the reaction of the compound of the formula [image] where X is according to the above definition, with the compound of the formula [image] and if X is not cyano optionally followed by conversion of the X group to a cyano group, followed by dehydration to form a compound of formula (III) and if X is not cyano, optionally followed by conversion of the X group to a cyano group. 3. The method according to claim 1, characterized in that the compound of the formula (III) is prepared by the reaction of the compound of the formula [image] where X is according to the above definition, with the compound of the formula [image] and if X is not cyano optionally followed by conversion of the X group to a cyano group, followed by dehydration to form a compound of formula (III) and if X is not cyano then optionally followed by conversion of the X group to a cyano group. 4. The method according to claim 1, characterized in that the compound of the formula is prepared by the reaction of the compound of the formula [image] where X is according to the above definition, with the compound of the formula [image] in order to create a compound of the formula [image] and if X is not cyano optionally followed by conversion of the X group to a cyano group, followed by peroxidation of the double bond to form an epoxide, and if X is not cyano, optionally by conversion of the X group to a cyano group and then reaction with dimethylamine or a salt thereof followed by dehydration in order to create a compound of formula (III) and if X is not cyano then the conversion of the group X to the cyano group optionally follows. 5. A compound characterized by having the formula [image] where X is a cyano group or a group that can be converted to a cyano group or an acid salt thereof. 6. A compound characterized by having the formula [image] where X is a cyano group or a group that can be converted to a cyano group or an acid salt thereof. 7. Antidepressant pharmaceutical composition characterized in that it contains citalopram produced by the method according to any one of claims 1 to 4.